Phenotype and Genotype of Autosomal Dominant Alzheimer's Disease in Jalisco, Mexico

墨西哥哈利斯科州常染色体显性阿尔茨海默病的表型和基因型

• 批准号: 10054049
• 负责人: JOHN M RINGMAN
• 金额: $ 68.22万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10054049
• 关键词: Adult; Advocacy; Affect; Age; Age of Onset; Alzheimer' s Disease; Amyloid Beta A4 Precursor Protein; C9ORF72; CSF1R gene; California; Clinic; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Cognitive; Collaborations; Colombia; Data Set; Development; Disease; Elements; Ethics; Evaluation; Extended Family; Family; Founder Effect; Functional disorder; Funding; Future; Gender; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic Screening; Genetic study; Genotype; Goals; Impaired cognition; Infrastructure; Inherited; International; Intervention; Leg; Measures; Medical Genetics; Mentorship; Mexican; Mexico; Mutation; Neurodegenerative Disorders; Neurologic; Neuropsychology; Onset of illness; Pathogenicity; Patient Care; Performance; Persons; Phase; Phenotype; Population; PrP gene; Presenile Alzheimer Dementia; Prevention; Procedures; Protocols documentation; Reporting; Research; Research Infrastructure; Research Personnel; Resources; Risk; Spastic Paraparesis; Standardization; System; Technology; Testing; Training; United States National Institutes of Health; Universities; Work; base; behavioral phenotyping; cognitive testing; cohort; disease phenotype; disease-causing mutation; evidence base; exome sequencing; genetic testing; genetic variant; improved; mutation carrier; presenilin-1; presenilin-2; presymptomatic testing; prospective; research clinical testing; research study; standardize measure

The study of persons with or at-risk for genetically-determined autosomal dominant Alzheimer’s disease (ADAD) due to mutations in the PSEN and APP genes has made tremendous contributions to our understanding of AD in general. As the future development of AD in persons inheriting ADAD mutations can be reliably predicted, one can define the disease phenotype and changes occurring during the presymptomatic phase of the disease with great sensitivity, enabling the evaluation of other factors influencing disease course (e.g. modifying genes, effects of putative disease-modifying interventions). Such research is facilitated by the identification of large families sharing the same genetic predisposition, an approach that has been best implemented in an extended family in Colombia with a common mutation in PSEN1 (E280A). A similar founder effect for a distinct mutation in PSEN1 (A431E) and another large family with a different ADAD-causing mutation in APP (V717I) has been identified in the State of Jalisco in Mexico but to date these families have been understudied. The goal of the current application is to facilitate the performance of clinical studies of this population by investigators in Jalisco. This will be achieved through the following specific aims: Specific Aim #1) To characterize and follow persons with and at-risk for ADAD in Jalisco by harmonizing measures between the Centro de Investigación Biomédica de Occidente Genetics clinic in Guadalajara, the University of Guadalajara Polyclinic in Tepatitlan, and the USC Alzheimer’s Disease Research Center. By providing gene-sequencing technology and training, we will also enable the genetic characterization of this population. Specific Aim #2) To perform studies to identify genes that affect the age of disease onset and the presence of leg stiffness in ADAD. Specific Aim #3) To improve the ability of clinicians and researchers in Jalisco to deliver presymptomatic genetic counseling for persons at-risk for ADAD, thus optimizing autonomy with regards to research participation. This project will improve our understanding of the pathophysiology of ADAD and lay the groundwork for future studies of this informative population in Mexico.

对患有遗传决定的常染色体显性阿尔茨海默病或有患该病风险的人的研究 PSEN 和 APP 基因突变引起的疾病 (ADAD) 做出了巨大贡献 我们对 AD 的一般理解。随着 ADAD 继承者中 AD 的未来发展 可以可靠地预测突变，可以定义疾病表型和发生的变化 在疾病的症状前阶段具有很高的敏感性，能够评估其他 影响疾病进程的因素（例如改变基因、假定的疾病缓解作用） 干预）。通过识别共享相同内容的大家庭，可以促进此类研究 遗传倾向，这种方法在哥伦比亚的大家庭中得到了最好的实施 PSEN1 (E280A) 具有常见突变。 PSEN1 的独特突变具有类似的奠基者效应 (A431E) 和另一个在 APP 中具有不同 ADAD 引起突变的大家族 (V717I) 已被 在墨西哥哈利斯科州发现，但迄今为止这些家庭尚未得到充分研究。目标 当前应用程序的目的是通过以下方式促进该人群的临床研究的进行 哈利斯科州的调查人员。这将通过以下具体目标来实现： 具体目标 #1) 通过以下方式描述和跟踪哈利斯科州患有 ADAD 的人和有 ADAD 风险的人 协调欧洲生物医学研究中心和遗传学诊所之间的措施 瓜达拉哈拉、特帕蒂特兰瓜达拉哈拉大学综合诊所和南加州大学阿尔茨海默病 研究中心。通过提供基因测序技术和培训，我们还将使 该群体的遗传特征。 具体目标 #2) 进行研究以确定影响疾病发病年龄和发病年龄的基因 ADAD 中存在腿部僵硬。 具体目标 #3) 提高哈利斯科州临床医生和研究人员提供服务的能力 为 ADAD 风险人群提供症状前遗传咨询，从而优化自主性 关于研究参与。 该项目将提高我们对 ADAD 病理生理学的理解，并奠定基础 为未来研究墨西哥这一信息丰富的人群奠定基础。